A nuclear blast or other mass casualty radiation event will necessarily cause multiorgan radiation toxicities compounded by physical trauma and thermal burns. Deaths will result from complex and combined organ injuries that occur in a time- and dose-dependent manner. While the strategic national stockpile includes agents for hematological acute radiation syndrome (H-ARS), no candidates are approved for gastrointestinal ARS (GI-ARS) and few if any candidates are approved for other organs. As cutaneous radiation injury [CRI (blistering, bleeding)] when combined with H/GI-ARS can lead to death, an agent that aids multiple epithelial tissues for combined injuries would be an ideal medical countermeasure. In light of the far-reaching potential of FGFs, we developed an FGF-2 peptide mimetic, FGF-PT; this alternative to the full-length protein is economical, easily scaled and synthesized, and has a long storage life. We hypothesize that the pluripotent effects of FGF-PT on epithelial, mesenchymal, and endothelial cells, which include preservation and proliferation of progenitor cells, maintenance of normal cellular maturation and function, and improved tissue perfusion, will mitigate combined radiation injury syndromes. We propose to test this hypothesis through the following Specific Aims: Aim 1: We will move FGF-PT toward an investigational new drug (IND) application for GI-ARS. We have already discussed the pre-IND process with representatives of NIAID, FDA, and BARDA. Based on this meeting, we propose a 6-step process to confirm mitigation benefit and mechanism of action in a GI-ARS/H- ARS model in Wistar Rats. Studies will include pharmacokinetics (PK), pharmacodynamics (PD), and toxicity testing in rats followed by PK and PD in Rhesus macaques to determine the drug dose and schedule for full good laboratory practice (GLP) testing in rats and macaques in separate follow-up studies. Aim 2: We have shown that FGFs can mitigate radiation dermatitis and improve platelet function following irradiation. In this aim, we will elucidate the role of both systemic and topical FGF-PT for CRI using an NIH Swiss model (strontium-90 beta burn) and Gttingen minipig model. In the minipig, we will test our models for allometric scaling between mouse, rat, monkey, and pig, and employ a radiation burn healing model (16 sites of 4x4 cm /minipig) developed by Core B. At the completion of Year 3, we expect to have sufficient knowledge of dose, schedule, mechanism of action, human relevance, and safety to design a ?pivotal? study for both the rat and monkey, according to the Animal Rule, for GI-ARS under GLP conditions. Funding for that study will be sought in Year 4. Near the completion of Year 4, we expect to have similar evidence for CRI. While minipigs are expected to play a key role, the CRI NIAID meeting this month (May 2019) has not yet recommended a model design. In Year 5, we will refine our approach to meet criteria more clearly defined at that time for FDA approval of agents for CRI.